The following discussion of the prior art is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however, reference to any prior art in this specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field.
Omeprazole is chemically known as 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulfonyl]-1H-benzimidazole. The S-enantiomer of omeprazole, “esomeprazole”, is chemically known as (S)-5-methoxy-2-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulfonyl]-1H-benzimidazole. Esomeprazole is a proton pump inhibitor used in the treatment of dyspepsia, peptic ulcer disease, gastroesophageal reflux disease and Zollinger-Ellison syndrome. Esomeprazole magnesium salt is marketed as NEXIUM® and is represented by Formula (I).

There are a large number of patents and patent applications disclosing different substituted 2-(2-pyridinylmethylsulphinyl)-1H-benzimidazoles. This class of compounds has properties making the compounds useful as inhibitors of gastric acid secretion and generally known as proton pump inhibitors.
For example, the compound (5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole), with the generic name omeprazole, described in EP 5129. It is marketed under the brand name Prilosec® for treatment of duodenal ulcer, gastric ulcer and GERD; maintenance of healing of errosive esophagitis, and long term treatment of pathological hyperscretory conditions.
Rabeprazole is another compound of the same class and chemically known by 2-[[[(4-(3-methoxypropoxy)-2-methyl-2-pyridinyl]methyl]sulfinyl-1H-benzimidazoles. It was reported in U.S. Pat. No. 5,045,552 and marketed in the United States under the brand name Aciphex® for healing of erosive or ulcerative GERD, maintenance of healing of GERD and treatment of symptomatic GERD.
Pantoprazole is the active ingredient of a pharmaceutical product that is marketed in the United States by Wyeth-Ayerst Inc. under the brand name Protonix®. Pantoprazole is chemically represented (5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]-sulfinyl]-1H-benzimidazole. Pantoprazole useful for short-term treatment of erosive esophagitis associated with gastroesophageal reflux disease (GERD), maintenance of healing of erosive esophagitis and pathological hypersecretory conditions including Zollinger-Ellison syndrome.
Lansoprazole, another compound represented by 2-[[[3-methyl-4(2,2,2,-trifluoroethoxy)-2-pyridiyl]methyl]sulfinyl]-1H-benzimidazole and reported in U.S. Pat. No. 4,628,098. It is marketed under the brand name Prevacid® for short-term treatment of duodenal ulcer, H. Pylori eradication to prevent recurrence of duodenal ulcer and maintenance of healed duodenal ulcers.
The single enantiomers of pharmacologically active compounds have met an increased interest in the last years because of improved pharmacokinetic and biological properties. Therefore, there is a demand and need for an enantioselective process that can be used in large scale for the manufacture of the single enantiomers of pharmacologically active compounds, such as for instance optically pure, substituted 2-(2-pyridinylmethylsulphinyl)-1H-benzimidazoles.
There are several patents and patent applications disclosing oxidation of prochiral sulfide. U.S. Pat. No. 5,948,789 describes oxidation of a pro-chiral sulfide with an oxidizing agent and chiral titanium complex in an organic solvent. U.S. Pat. No. 6,166,213 describes a process for the preparation of omeprazole by oxidation of pyrmetazole in the presence of meta-chloroperoxybenzoic acid. U.S. Patent Application No. 2003/0171591 discloses a method of producing benzimidazoles comprising oxidizing sulfide with an excess of oxidizing agent in the presence of a catalyst for asymmetric induction.
U.S. Pat. No. 6,229,021 describes a process for the preparation of omeprazole comprising oxidizing its corresponding thioether with peroxyacetic acid in a two-phase water and chlorinated organic solvent medium.
U.S. Pat. No. 6,268,502 describes a process for the preparation of omeprazole comprising oxidizing its corresponding thioether with 3-chloroperoxybenzoic acid in ethyl acetate. U.S. Pat. No. 6,603,009 discloses a process for the preparation of omeprazole comprising oxidizing its corresponding thioether with sodium percarbonate and molybdenum salt catalyst. U.S. Pat. No. 5,386,032 discloses a process for the preparation of omeprazole comprising oxidizing its corresponding thioether with m-chloroperoxybenzoic acid at specific pH.
U.S. Pat. No. 7,915,422 B2 discloses the enantioselective catalytic oxidation process for of a pro-chiral sulfide with an oxidizing agent in presence of chiral transition metal complex and a base in the absence of an organic solvent.
U.S. Patent Application No. 2010/0210848 A1 discloses the process for preparation of optically active sulfoxide compounds by asymmetrically oxidizing prochiral sulphide compounds in presence of chiral transition metal complex in water and in presence of a base.
International (PCT) publication WO 2003/089408 A2 discloses an enantioselective catalytic oxidation process for the preparation of on optically active enantiomer or an enantiomerically enriched form of substituted pyridinylmethylsulphinyl-benzimidazole with an oxidizing agent in an organic solvent in the presence of a base and a catalyst comprising titanium or vanadium complexed with a chiral mondenate ligand.
International (PCT) publication WO 99/47514 A2 discloses a method of producing benzimidazole compounds comprising oxidizing its corresponding thioether with perborate salt.
International (PCT) publication WO 03/089408 A2 describes an enantioselective catalytic oxidation of sulfide with an oxidizing agent, in an organic solvent, base and in the presence of titanium or vanadium complexed with a monodentate ligand.
International (PCT) publication WO 2008/018091A1 discloses the process for producing sulphoxide compounds in either as a single enantiomer or in an enantiomerically enriched form by asymmetrically oxidizing a prochiral sulfide with an oxidizing agent and a chiral transition metal complex without using an organic solvent and a base.
International (PCT) publication WO 2010/0134099 A1 discloses a one-pot process for the preparation of omeprazole and related compounds.
Each and every reference in the prior art literature of which the inventors are aware discloses the process for the preparation of esomeprazole or other related chiral sulfoxide benzimidazole derivatives either by isolation of alkali metal salts of esomeprazole and converting to magnesium salt or by use of pyrmetazole as a prochiral sulfide as a starting material. No prior art literature which the inventors are aware discloses one pot process for the preparation of esomeprazole magnesium dihydrate starting from 2-(chloromethyl)-3,5-dimethyl-4-methoxy pyridine hydrochloride of Formula (V).
In view of the above, there is provided a one pot process for preparing benzimidazole derivatives and pharmaceutically acceptable salts thereof. In particular, the invention provides one pot process for enantioselective synthesis of single enantiomers of substituted sulphoxides 2-(2-pyridinylmethylsulphinyl)-1H-benzimidazoles or said compounds in an enantiomerically enriched form. More particularly, the invention provides one pot process for the preparation of esomeprazole magnesium dihydrate. Such improved processes and benzimidazole derivatives prepared thereby are now provided by the present invention substantially as herein described.